B-type chronic lymphocytic leukemia (B-CLL) is the most prevalent leukemia in the Western world. Although B-CLL was long considered a homogeneous disease, recent studies indicate that B-CLL cases can be divided into two subgroups based on Ig V gene mutation status and also based on surface membrane expression of CD38. Patients in these two follow strikingly different clinical courses. Those patients in the unmutated Ig V gene group and those in the CD38+ experience a much more aggressive disease and almost invariably dying, despite extensive chemotherapy, much sooner than the patients in the mutated Ig V gene group or in the CD38- group. The reasons for these differences in clinical outcome are unknown. This proposal is designed to understand more precisely how these categories of B-CLL cases differ. We will address this by determining differences in the characteristics of the B-CLL cells, and some of the other immune cells, in these two groups. Specifically, we will determine: [1] the phenotypic and molecular features of B cell activation and differentiation that are unique to each B-CLL subgroup, [2] the biologic features that might explain the different clinical courses of the B-CLL subgroups, in particular whether the two subsets of B-CLL cells exhibit differences in immunologic properties such as cytokine production, antigen presentation, and cell signaling and apoptosis induction via the B cell receptor in conjunction with other signaling pathways, and [3] the patterns and levels of gene expression that distinguish the B-CLL subgroups, either unmanipulated or after BCR signaling, as measured by cDNA-based representation difference analyses and microarray gene chip technologies. We believe that the proposed studies will identify critical differences in cell maturation, immune function, and gene expression that will help clarify the reasons for their dramatically dissimilar clinical courses. Hopefully, these differences will provide important basic and clinical insights into this disease and suggest future prognostic and therapeutic approaches to it.